title: Synthesis and properties of star-comb polymers and their doxorubicin conjugates.
abstract: We describe a six-step synthesis to water-soluble doxorubicin (DOX)-loaded biodegradable PEGylated star-comb polymers with favorable pharmaceutical properties by atom transfer radical polymerization (ATRP) starting with a commercially available tripentaerythritol carrying eight reactive sites. The low polydispersity polymers degrade in a stepwise manner into lower molecular weight (MW) fragments by 15 days at 37 °C at either pH 5.0 or pH 7.4. The half-life of the star-comb polymers in blood is dependent upon the molecular weight; the 44 kDa star-comb has a t(1/2, β) of 30.5 ± 2.1 h, which is not significantly changed (28.6 ± 2.7 h) when 6.6 wt % of DOX is attached to it via a pH-sensitive hydrazone linker. The star-comb polymers have low accumulation in organs but a high accumulation in C26 flank tumors implanted in Balb/C mice. The hydrodynamic diameter of polymer-DOX conjugates measured by dynamic light scattering increases from 8 to 35 to 41 nm as the loading is increased from 6.6 to 8.4 to 10.2 wt %. Although there is no significant difference in the t(1/2, β) or in the accumulation of polymer-DOX in C-26 tumors, the uptake of polymer in the spleen is significantly higher for polymers with DOX loadings greater than 6.6 wt %. Polymer accumulation in other vital organs is independent of the DOX loading. The facile synthesis, biodegradability, long circulation time, and high tumor accumulation of the attached drug suggests that the water-soluble star-comb polymers have promise in therapeutic applications.
authors.affiliation: Department of Bioengineering, Therapeutic Sciences and Pharmaceutical Chemistry, University of California, San Francisco , California 94143-0912, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Derek G
authors.initials: DG
authors.lastname: van der Poll
authors.forename: Katherine
authors.initials: K
authors.lastname: Jerger
authors.forename: William C
authors.initials: WC
authors.lastname: Floyd
authors.forename: Jean M J
authors.initials: JM
authors.lastname: Fréchet
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000737:chemistry*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D013499:Surface Properties; D014018:Tissue Distribution
chemical_list: D011092:Polyethylene Glycols; D004317:Doxorubicin